Inhibition Of Voluntary Ethanol Consumption With Non-Peptidyl Melanocortin-4 Receptor Agonists

ABSTRACT

The present invention relates to methods of inhibiting or reducing voluntary alcohol consumption in a subject comprising administering a non-peptidyl melanocortin 4 receptor agonist to said subject. The present invention further relates to methods of treating or preventing alcoholism, alcohol abuse, and alcohol related disorders in a subject comprising administering a non-peptidyl melanocortin 4 receptor agonist to said subject. The present invention further provides for pharmaceutical compositions and medicaments useful in carrying out these methods.

BACKGROUND OF THE INVENTION

Alcohol abuse is one of the most significant problems in modern society.Nearly 14 million people in the United States, approximately 1 in every13 adults, abuse alcohol or are alcoholics (U.S. Dept. of HumanServices, 2001 National Household Survey on Drug Abuse: Volume 1(BKD461, SMA 02-3758)). According to the National Institutes of Health,each year alcohol abuse accounts for 45% of all car crash fatalities(over 20,000 individuals) and is involved in approximately 44% of allshort-stay hospital visits. An additional 26,000 individuals die fromalcohol-associated chronic liver disease and cirrhosis of the liver(NCHS, National Vital Statistics Report Vol. 50, No. 5, 2000). TheJustice Department reported that alcohol was involved in nearly 40% ofall violent crimes in 1998. The resulting economic cost of alcohol abuseto the United States is estimated to be nearly $150 billion per year.

The causes of alcoholism are not fully known. Genetics may play a role;a family history of alcoholism makes it more likely for a person todevelop alcoholism if that person chooses to drink. Certainenvironmental risk factors may also influence whether a person with agenetic risk for alcoholism ever develops the disease.

Alcohol problems may be classified into two categories, alcoholism oralcohol dependence, and alcohol abuse. Alcoholism is a dependence onalcohol and is characterized by abnormal alcohol seeking behavior thatleads to impaired control over drinking. Alcohol abuse is characterizedby drinking too much or too often, without being an alcoholic. Alcoholmisuse has also been found to predispose the subject to osteoporosis,slow bone healing, impaired wound healing, inhibited osteoblasticfunction and diminished immune defenses. Alcohol intoxication increasesthe risk of further accidents, and decreases the pain inhibition thatwould make a normal patient more careful. Alcohol dependence also leadsto altered cognitive and emotional functions, such as impaired judgment,feelings of incompetency, low self-esteem, despair in relationships,feelings of failure, and depression.

Several medications are currently used to treat alcoholism. Disulfuram(Antabuse®) and Naltrexone (Trexan®) are the only FDA approved productsthat are currently available for adjunctive use in the treatment ofalcohol abuse. Disulfuram works by blocking the intermediary metabolismof alcohol in the body to produce a build up of acetaldehyde, which inturn produces markedly adverse behavioral and physiological effects,such as severe nausea and vomiting. Patient compliance in taking thedrug is poor due to these side effects (see T W Rall, in: Goodman andGilman's The Pharmacological Basis of Therapeutics, A G Gilman et al,8th Edition, Chap 17, pp 378-379). Naltrexone is a well-known opioidreceptor antagonist and is thought to reduce the positive reinforcingeffects of ethanol by blocking the effects of endogenous opioids andreducing alcohol stimulated dopamine release. In practice, naltrexone isonly moderately effective because it is relatively short acting andpatients require co-treatment with behavioral therapy for the drug tohave any effect (J R Volpicelli et al, Arch Gen Psychiatry, 1992,49:876-880). Acamprosate, which is not currently approved for use in theUnited States, is believed to minimize the negative side-effectsassociated with protracted abstinence by potentiating GABA andattenuating glutamate release. Benzodiazepines (Valium®, Librium®) arealso sometimes useful during the first days after patients stop drinkingto help them safely withdraw from alcohol; however, these medicationscan not be used for longer periods because benzodiazepines may alsoproduce dependence in patients. As a result, there is a continuing needto develop new compounds that are useful for the treatment of alcoholismand alcohol abuse in mammals.

Recent studies support a role for melanocortin signaling in behavioraland neurochemical actions of ethanol. The melanocortin (MC) system iscomposed of peptides that are cleaved from the polypeptide precursor,proopiomelanocortin (POMC). These peptides include adrenocorticotropichormone (ACTH), α-melanocyte stimulating hormone (α-MSH), β-MSH, andγ-MSH. Brain melanocortin peptides are produced primarily by neuronswithin the hypothalamic arcuate nucleus, the nucleus of the solitarytract, and the medulla. Genetic and pharmacological evidence revealsthat melanocortin signaling is involved with grooming behavior,antipyretic and anti-inflammatory responses, learning, reproductivefunction, and regulation of appetite and energy homeostasis.

A recent report found significant differences in brain melanocortin 3and melanocortin 4 receptor levels between rats selectively bred forhigh ethanol consumption (AA) and low ethanol consumption (ANA). AA ratsselectively bred for high ethanol drinking have lower levels ofmelanocortin 3 receptor in the shell of the nucleus accumbens whencompared with controls, but have high levels of melanocortin 3 receptor(MC3R) and melanocortin 4 receptor (MC4R) in various regions of thehypothalamus (Lindblom et al., Phann Biochein Behav 72:491-496, 2002).It has been shown that central infusion of the non-selectivemelanocortin agonist, MTII, significantly reduces voluntary ethanoldrinking and prevents ethanol-induced changes in endogenous opioidpeptide levels in the substantia nigra and VTA of AA rats with anestablished ethanol intake (Ploj et al., Brain Res Bull, 59:97-104,2002). It was suggested that melanocortin signaling may regulate ethanoldrinking by modulating endogenous opioid activity within mesolimbicdopamine pathways (Ploj et al., Brain Res Bull, 59:97-104, 2002).However, a recent report indicated that a MC4R-selective antagonist(HS014) has no effect on ethanol drinking by AA rats (Ploj et al., BrainRes Bull, 59:97-104, 2002).

It is unclear which melanocortin receptor(s) are important formodulating MTII-induced reductions of ethanol consumption (Ploj et al.,Brain Res Bull, 59:97-104, 2002). MTII is a non-selective melanocortinagonist that binds, with varying affinity, to all centrally expressedmelanocortin receptors (MC1R, MC2R, MC3R, MC4R and MC5R), but has thegreatest affinity for MC3R and MC4R (Haskell-Luevano et al., J. Med.Chem. 40:1738-1748, 1997; Schioth et al., Peptides, 18:1009-1013, 1997).It is also possible that melanocortin 1 receptor (MC1R) and/ormelanocortin 5 receptor (MC5R) are involved, as MTII binds to both ofthese receptors (Haskell-Luevano et al., J. Med. Chem. 40:1738-1748,1997; Schioth et al., Peptides, 18:1009-1013, 1997). MC1R is expressedspecifically in periaqueductal gray (PG) region of the brain (Xia etal., NeuroReport, 6:2193-2196, 1995) while MC5R is found in severalbrain regions, including the NAc (Griffon et al., Biochem Biophys ResCom, 200:1007-1014, 1994).

There is a need for an effective therapy for the treatment or preventionof alcoholism, alcohol abuse and alcohol related disorders.

It has now been found that non-peptidyl melanocortin 4 receptor agonistsare useful to inhibit alcohol self-administration and consumption. Theselective melanocortin 4 receptor agonists of the present invention arebeneficial over non-selective melanocortin agonists since selective MC4Ragonists do not exhibit the side effects associated with non-selectiveMC4R agonists, such as melanocortin 1 mediated pigment changes andworsening of acne associated with MC5R agonists. Additionally, the useof non-peptidyl melanocortin-4 receptor agonists for the treatment ofalcoholism and related disorders is beneficial over the use of peptidylmelanocortin 4 agonists since peptidyl MC4R agonists are typicallydegraded in the stomach and GI tract, and are therefore not orallybioavailable, and brain penetration of small molecules is better.

It is an object of the present invention to identify methods ofinhibiting alcohol consumption comprising administering a non-peptidylmelanocortin 4 receptor agonist to a subject. It is another object ofthe present invention to identify methods of treating alcoholism andalcohol abuse comprising administering a non-peptidyl melanocortin 4receptor agonist to a subject. It is yet another object of the inventionto identify methods of preventing alcoholism, alcohol abuse, andalcohol-related disorders. It is a further object of the presentinvention to provide a method of manufacture of a medicament useful toinhibit alcohol consumption.

SUMMARY OF THE INVENTION

The present invention provides a method of inhibiting alcoholconsumption comprising administration of a therapeutically effectiveamount of a non-peptidyl melanocortin 4 receptor agonist to a subject.

The present invention further provides a method of reducing alcoholconsumption comprising administration of a therapeutically effectiveamount of a non-peptidyl melanocortin 4 receptor agonist to a subject.

The present invention further provides a method of preventing alcoholconsumption comprising administration of a therapeutically effectiveamount of a non-peptidyl melanocortin 4 receptor agonist to a subject.

The present invention also provides a method of treating or preventingalcoholism comprising administration of a therapeutically effectiveamount of a non-peptidyl melanocortin 4 receptor agonist to a subject.

The present invention also provides a method of treating or preventingalcohol abuse comprising administration of a therapeutically effectiveamount of a non-peptidyl melanocortin 4 receptor agonist to a subject.

The present invention further provides a method of treating orpreventing alcohol-related diseases comprising administration of atherapeutically effective amount of a non-peptidyl melanocortin 4receptor agonist to a subject.

The present invention is also concerned with treatment of theseconditions, and the use of the compounds and compositions of the presentinvention for manufacture of a medicament useful for treating theseconditions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Operant training for oral ethanol across 30 minute test sessionsin rats (n=8-10). Rats were trained on a continuous reinforcement (FR-1)schedule using a saccharine fading procedure and once stable levels ofethanol self-administration (10% w/v) were achieved, testing wasinitiated. Test 1 examined the effects of melanocortin 4 receptoragonist, Compound A, on maintenance levels of ethanolself-administration and Test 2 examined the effects of Compound A on theAlcohol Deprivation Effect (ADE).

FIG. 2. Animal Model of Alcohol Reward: shows the mean ethanol consumedin a 30 minute discrete trial session. Operant training for oral ethanolin 30 minute test sessions in rats (n=8-10). Melanocortin 4 receptoragonist, Compound A, was administered at 0, 5, 10 or 20 mg/kg, po priorto testing. A significant reduction in ethanol self-administration wasobserved following 20 mg/kg. Water consumption was not significantlychanged following any dose of Compound A. Ethanol consumed isrepresented as means ±SEM. The symbol * indicates a significantdifference between the vehicle and drug treated groups (p<0.05).

FIG. 3. Animal Model of Alcohol Relapse: shows the attenuation of theAlcohol Deprivation Effect (ADE). Operant training for oral ethanol in30 minute test sessions in rats (n=8-10). Following the maintenanceself-administration test, rats were rebaselined prior to being confinedto their home-cages for a 10 day deprivation period. Melanocortin 4receptor agonist, Compound A was administered at 0, 5, 10 or 20 mg/kg,po prior to reintroduction to the test chambers following deprivation. Asignificant attenuation of the alcohol deprivation effect was observedfollowing 5 and 10 mg/kg and a further reduction below baseline levelswas observed following 20 mg/kg. Water consumption was not significantlychanged following any dose of Compound A. Ethanol consumed isrepresented as means ±SEM. The symbol * indicates a significantdifference between baseline and drug treated groups (p<0.05). The symbol# indicates a significant difference between vehicle treated (ADE) anddrug treated groups (p<0.05).

DETAILED DESCRIPTION OF THE INVENTION

The present invention shows that nonpeptidyl, selective melanocortin 4receptor agonists inhibit alcohol self-administration and consumption.It was found that the selective melanocortin-4 receptor agonist,Compound A, dose dependently reduced ethanol self administration byapproximately 50% in male Wistar rats (See FIG. 2). It was also foundthat Compound A reduced the increase in ethanol consumption typicallyseen after a 10 day period of forced deprivation (the alcoholdeprivation effect (ADE)) in male Wistar rats (See FIG. 3). Alcoholdeprivation effect (ADE) is the transient increase in oral ethanol selfadministration following forced deprivation, and is characterized byloss of control over intake. ADE is precipitated by re-exposure toalcohol related cues after a period of alcohol deprivation. Thesestudies show that selective melanocortin 4 receptor agonists block theacute reinforcing effects of alcohol. As a result, treatment with aselective melanocortin agonist resulted in a significant reduction ofvoluntary ethanol consumption in rats, as well as a prevention of thesignificant elevation in consumption observed after a brief deprivationperiod (ADE). Additionally, MC4R agonist Compound A had no significanteffects on water consumption suggesting its effects on consumption arespecific to ethanol and not a general decrease in consummatory behavior.

The present invention provides a method of inhibiting alcohol selfadministration. The present invention also provides a method ofinhibiting alcohol consumption. The present invention also provides amethod of inhibiting alcohol consumption in a subject currentlyconsuming alcohol. The present invention further provides a method ofreducing alcohol consumption. The present invention further provides amethod of reducing alcohol consumption in a subject currently consumingalcohol. The present invention further provides a method of treating orpreventing alcoholism. The present invention further provides a methodof treating or preventing alcohol abuse. The present invention alsoprovides a method of treating or preventing alcohol-related disorders.The present invention further provides a significant reduction involuntary alcohol consumption. The present invention further provides amethod of preventing a relapse of alcohol consumption at pre-treatmentlevels following a period of alcohol deprivation. The present inventionfurther provides a method of reducing the amount of alcohol consumed asthe result of a relapse of alcohol consumption. The present inventionalso relates to pharmaceutical compositions, and medicaments useful forcarrying out these methods.

The methods of the present invention comprise a non-peptidylmelanocortin 4 receptor agonist. The melanocortin 4 receptor agonist ofuse in the present invention is selected from any non-peptidylmelanocortin 4 receptor agonist known in the art. Additionally, thenon-peptidyl melanocortin 4 receptor agonist may be a selectivemelanocortin 4 agonist. For convenience, the use of an orally activenon-peptidyl selective melanocortin 4 receptor agonist is preferred. Tofacilitate dosing, it is preferred that the melanocortin 4 receptoragonist is a long acting melanocortin 4 receptor agonist.

In one embodiment of the present invention, the invention is directed toa method of inhibiting alcohol consumption comprising administering atherapeutically effective amount of a non-peptidyl melanocortin 4receptor agonist, or a pharmaceutically acceptable salt thereof, to asubject in need thereof. In another embodiment of the present invention,the invention is directed to a method of inhibiting alcohol consumptioncomprising administering a therapeutically effective amount of anon-peptidyl selective melanocortin 4 receptor agonist, or apharmaceutically acceptable salt thereof, to a subject in need thereof.In another embodiment of the present invention, the invention isdirected to a method of inhibiting the alcohol deprivation effectcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a non-peptidyl selective melanocortin 4 receptoragonist, or a pharmaceutically acceptable salt thereof. In anotherembodiment of the present invention, the invention is directed to amethod of inhibiting alcohol consumption in a subject currentlyconsuming alcohol comprising administering to the subject atherapeutically effective amount of a non-peptidyl selectivemelanocortin 4 receptor agonist, or a pharmaceutically acceptable saltthereof.

In another embodiment of the present invention, the invention isdirected to a method of inhibiting the alcohol deprivation effect in asubject currently consuming alcohol comprising administering to thesubject a therapeutically effective amount of a non-peptidyl selectivemelanocortin 4 receptor agonist, or a pharmaceutically acceptable saltthereof.

In another embodiment of the present invention, the invention isdirected to a method of reducing alcohol consumption comprisingadministering a therapeutically effective amount of a non-peptidylmelanocortin 4 receptor agonist, or a pharmaceutically acceptable saltthereof, to a subject in need thereof. In a class of this embodiment,the reduction of alcohol consumption is the reduction of voluntaryalcohol consumption.

In another embodiment of the present invention, the invention isdirected to a method of reducing the amount of alcohol consumed as theresult of a relapse of alcohol consumption comprising administering atherapeutically effective amount of a non-peptidyl melanocortin 4receptor agonist, or a pharmaceutically acceptable salt thereof, to asubject in need thereof.

In another embodiment of the present invention, the invention isdirected to a method of reducing alcohol consumption in a subjectcurrently consuming alcohol comprising administering to the subject atherapeutically effective amount of a non-peptidyl melanocortin 4receptor agonist, or a pharmaceutically acceptable salt thereof. Inanother embodiment of the present invention, the invention is directedto a method of reducing alcohol consumption in a subject currentlyconsuming alcohol comprising administering to the subject atherapeutically effective amount of a non-peptidyl selectivemelanocortin 4 receptor agonist, or a pharmaceutically acceptable saltthereof.

In another embodiment of the present invention, the invention isdirected to a method of treating or preventing alcoholism comprisingadministering a therapeutically effective amount of a non-peptidylmelanocortin 4 receptor agonist, or a pharmaceutically acceptable saltthereof, to a subject in need thereof.

In another embodiment of the present invention, the invention isdirected to a method of treating or preventing alcohol abuse comprisingadministering a therapeutically effective amount of a non-peptidylmelanocortin 4 receptor agonist, or a pharmaceutically acceptable saltthereof, to a subject in need thereof.

In another embodiment of the present invention, the invention isdirected to a method of treating or preventing alcohol-related disorderscomprising administering a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.

In another embodiment of the present invention, the invention isdirected to a method of preventing a relapse of alcohol consumption topre-treatment levels following a period of alcohol deprivationcomprising administering a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.

In another embodiment of the present invention, the invention isdirected to a method of maintaining abstinence in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of a non-peptidyl selective melanocortin 4 receptoragonist, or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention isdirected to a method of reducing alcohol consumption comprisingadministering to a subject a therapeutically effective amount of anon-peptidyl selective melanocortin 4 receptor agonist, or apharmaceutically acceptable salt thereof, wherein the functionalactivity of the melanocortin 4 receptor agonist is characterized by anEC₅₀ at least 14-fold more selective for the human melanocortin 4receptor than for the human melanocortin 1 receptor, human melanocortin2 receptor, the human melanocortin 3 receptor and the human melanocortin5 receptor. In another embodiment of the present invention, theinvention is directed to a method of reducing alcohol consumptioncomprising administering to a subject a therapeutically effective amountof a non-peptidyl selective melanocortin 4 receptor agonist, or apharmaceutically acceptable salt thereof, wherein the functionalactivity of the melanocortin 4 receptor agonist is characterized by anEC₅₀ at least 65-fold more selective for the human melanocortin 4receptor than for the human melanocortin 1 receptor, human melanocortin2 receptor, the human melanocortin 3 receptor and the human melanocortin5 receptor. In another embodiment of the present invention, theinvention is directed to a method of reducing alcohol consumptioncomprising administering to a subject a therapeutically effective amountof a non-peptidyl selective melanocortin 4 receptor agonist, or apharmaceutically acceptable salt thereof, wherein the functionalactivity of the melanocortin 4 receptor agonist is characterized by anEC₅₀ at least 200-fold more selective for the human melanocortin 4receptor than for the human melanocortin 1 receptor, human melanocortin2 receptor, the human melanocortin 3 receptor and the human melanocortin5 receptor.

In a class of these embodiments, the functional activity of themelanocortin 4 agonist is characterized by an EC₅₀ at least 14-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 1 receptor. In another class of these embodiments, thefunctional activity of the melanocortin 4 agonist is characterized by anEC₅₀ at least 120-fold more selective for the human melanocortin 4receptor than for the human melanocortin 1 receptor.

In another class of these embodiments, the functional activity of themelanocortin 4 agonist is characterized by an EC₅₀ at least 100-foldmore selective for the human melanocortin 4 receptor than for the humanmelanocortin 2 receptor. In another class of these embodiments, thefunctional activity of the melanocortin 4 agonist is characterized by anEC₅₀ at least 700-fold more selective for the human melanocortin 4receptor than for the human melanocortin 2 receptor.

In another class of these embodiments, the functional activity of themelanocortin 4 agonist is characterized by an EC₅₀ at least 30-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 3 receptor. In another class of these embodiments, thefunctional activity of the melanocortin 4 agonist is characterized by anEC₅₀ at least 65-fold more selective for the human melanocortin 4receptor than for the human melanocortin 3 receptor.

In another class of these embodiments, the functional activity of themelanocortin 4 agonist is characterized by an EC₅₀ at least 50-fold moreselective for the human melanocortin 4 receptor than for the humanmelanocortin 5 receptor. In another class of these embodiments, thefunctional activity of the melanocortin 4 agonist is characterized by anEC₅₀ at least 90-fold more selective for the human melanocortin 4receptor than for the human melanocortin 5 receptor.

In another embodiment of the present invention, the invention isdirected to a method of reducing alcohol consumption comprisingadministering to a subject a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist, or a pharmaceuticallyacceptable salt thereof, wherein the binding affinity index of themelanocortin 4 receptor agonist is characterized by an IC₅₀ value atleast 35-fold more selective for the human melanocortin 4 receptor thanfor the human melanocortin 1 receptor, the human melanocortin 3 receptorand the human melanocortin 5 receptor.

In a class of this embodiment, the binding affinity index of themelanocortin 4 agonist is characterized by an IC₅₀ value at least125-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 1 receptor.

In another class of this embodiment, the binding affinity index of themelanocortin 4 agonist is characterized by an IC₅₀ value at least35-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 3 receptor. In another class of this embodiment,the binding affinity index of the melanocortin 4 agonist ischaracterized by an IC₅₀ value at least 160-fold more selective for thehuman melanocortin 4 receptor than for the human melanocortin 3receptor.

In another class of this embodiment, the binding affinity index of themelanocortin 4 agonist is characterized by an IC₅₀ value at least12-fold more selective for the human melanocortin 4 receptor than forthe human melanocortin 5 receptor. In another class of this embodiment,the binding affinity index of the melanocortin 4 agonist ischaracterized by an IC₅₀ value at least 35-fold more selective for thehuman melanocortin 4 receptor than for the human melanocortin 5receptor.

In another embodiment of the present invention, the invention isdirected to the use of a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist for the manufacture of amedicament useful to inhibit alcohol consumption in a subject in need ofsuch treatment.

In another embodiment of the present invention, the invention isdirected to the use of a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist for the manufacture of amedicament useful to reduce alcohol consumption in a subject in need ofsuch treatment. In a class of this embodiment, the alcohol consumptionis voluntary alcohol consumption.

In another embodiment of the present invention, the invention isdirected to the use of a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist for the manufacture of amedicament useful to treat or prevent alcoholism in a subject in need ofsuch treatment.

In another embodiment of the present invention, the invention isdirected to the use of a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist for the manufacture of amedicament useful to treat or prevent alcohol abuse in a subject in needof such treatment.

In another embodiment of the present invention, the invention isdirected to the use of a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist for the manufacture of amedicament useful to treat or prevent alcohol-related disorders in asubject in need of such treatment.

In another embodiment of the present invention, the invention isdirected to the use of a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist for the manufacture of amedicament useful to prevent a relapse of alcohol consumption topre-treatment levels following a period of alcohol deprivation in asubject in need of such treatment.

In another embodiment of the present invention, the invention isdirected to the use of a therapeutically effective amount of anon-peptidyl melanocortin 4 receptor agonist for the manufacture of amedicament useful to prevent reducing the amount of alcohol consumed asthe result of a relapse of alcohol consumption in a subject in need ofsuch treatment.

Melanocortin 4 receptor agonists useful in the methods and medicamentsof the present invention are represented by the compounds of structuralFormula I and II:

or a pharmaceutically acceptable salt thereof; whereinX is selected from the group consisting of: C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl,(CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N, (CH₂)_(n)CON(R⁵R⁵), (CH₂)_(n)CO₂R⁵,(CH₂)_(n)COR⁵, (CH₂)_(n)NR⁵C(O)R⁵, (CH₂)_(n)NR⁵CO₂R⁵,(CH₂)_(n)NR⁵C(O)N(R⁵)₂, (CH₂)_(n)NR⁵SO₂R⁵, (CH₂)_(n)S(O)_(p)R⁵,(CH₂)_(n)SO₂N(R⁵)(R⁵), (CH₂)_(n)OR⁵, (CH₂)_(n)OC(O)R⁵,(CH₂)_(n)OC(O)OR⁵, (CH₂)_(n)OC(O)N(R⁵)₂, (CH₂)_(n)N(R⁵)(R⁵), and(CH₂)_(n)NR⁵SO₂N(R⁵)(R⁵), wherein heteroaryl is as defined above;phenyl, naphthyl, and heteroaryl are unsubstituted or substituted withone to three groups independently selected from R⁶; alkyl, cycloalkyl,and heterocyclyl are unsubstituted or substituted with one to threegroups independently selected from R⁶ and oxo; and wherein any methylene(CH₂) in X is unsubstituted or substituted with one to two groupsindependently selected from halogen, hydroxy, and C₁₋₄ alkyl;Y is selected from the group consisting of: hydrogen, C₁₋₈ alkyl, C₂₋₆alkenyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl,(CH₂)_(n)-heteroaryl, and (CH₂)_(n)-heterocyclyl,wherein heteroaryl is as defined above, and phenyl, naphthyl, andheteroaryl are unsubstituted or substituted with one to three groupsindependently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl areoptionally substituted with one to three groups independently selectedfrom R⁶ and oxo; and wherein any methylene (CH₂) in Y is unsubstitutedor substituted with one to two groups independently selected fromhalogen, hydroxy, and C₁₋₄ alkyl;R¹ is selected from the group consisting of: hydrogen, amidino, C₁₋₄alkyliminoyl, C₁₋₁₀ alkyl, (CH₂)_(n)—C₃₋₇ cycloalkyl, (CH₂)_(n)-phenyl,(CH₂)_(n)-naphthyl, and (CH₂)_(n)-heteroaryl, wherein heteroaryl isselected from the group consisting of (1) pyridinyl, (2) furyl, (3)thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8)pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12)pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16)benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20)benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, andheteroaryl are unsubstituted or substituted with one to three groupsindependently selected from R³; and alkyl and cycloalkyl areunsubstituted or substituted with one to three groups independentlyselected from R³ and oxo;R² is selected from the group consisting of: phenyl, naphthyl, andheteroaryl, wherein heteroaryl is selected from the group consisting of:(1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6)thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10)isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14)quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18)benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl;in which phenyl, naphthyl, and heteroaryl are unsubstituted orsubstituted with one to three groups independently selected from R³;each R³ is independently selected from the group consisting of: C₁₋₆alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl,(CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴,(CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴,(CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂,(CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴,(CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂,(CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, andOCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl,heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted orsubstituted with one to three substituents independently selected fromhalogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; andwherein any methylene (CH₂) carbon atom in R³ is unsubstituted orsubstituted with one to two groups independently selected from halogen,hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene(CH₂) group are taken together with the carbon atom to which they areattached to form a cyclopropyl group;each R⁴ is independently selected from the group consisting of:hydrogen, C₁₋₆ alkyl, (CH₂)_(n) phenyl, (CH₂)_(n)-heteroaryl,(CH₂)_(n)-naphthyl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl,and (CH₂)_(n)C₃₋₇ bicycloalkyl, wherein alkyl, phenyl, heteroaryl,heterocyclyl, and cycloalkyl are unsubstituted or substituted with oneto three groups independently selected from halogen, C₁₋₄ alkyl,hydroxy, and C₁₋₄ alkoxy; or two R⁴ groups together with the atom towhich they are attached form a 4- to 8-membered mono- or bicyclic ringsystem optionally containing an additional heteroatom selected from O,S, and NC₁₋₄ alkyl;each R⁵ is independently selected from the group consisting of:hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl,(CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇ cycloalkyl, wherein heteroarylis as defined above; phenyl, naphthyl, and heteroaryl are unsubstitutedor substituted with one to three groups independently selected from R³;alkyl and cycloalkyl are unsubstituted or substituted with one to threegroups independently selected from R³ and oxo; and wherein any methylene(CH₂) in R⁵ is unsubstituted or substituted with one to two groupsindependently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two R⁵groups together with the atom to which they are attached form a 5- to8-membered mono- or bicyclic ring system optionally containing anadditional heteroatom selected from O, S, and NC₁₋₄ alkyl;each R⁶ is independently selected from the group consisting of: C₁₋₆alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl,(CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴,(CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴,(CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂,(CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴,(CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂,(CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, andOCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl,heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted orsubstituted with one to three substituents independently selected fromhalogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; andwherein any methylene (CH₂) carbon atom in R⁶ is unsubstituted orsubstituted with one to two groups independently selected from halogen,hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene(CH₂) group are taken together with the carbon atom to which they areattached to form a cyclopropyl group;r is 1 or 2;s is 0, 1, or 2;n is 0, 1 or 2; andp is 0, 1, or 2.

In one embodiment of the compounds of structural formula I and II, R¹ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, (CH₂)₀₋₁C₃₋₆cycloalkyl, and (CH₂)₀₋₁-phenyl; wherein phenyl is unsubstituted orsubstituted with one to three groups independently selected from R³; andalkyl and cycloalkyl are optionally substituted with one to three groupsindependently selected from R³ and oxo. In a class of this embodiment,R¹ is tert-butyl.

In a second embodiment of the compounds of structural formula I and II,R² is phenyl or thienyl optionally substituted with one to three groupsindependently selected from R³. In a class of this embodiment, R² isphenyl optionally substituted with one to three groups independentlyselected from R³. In another class of this embodiment, R² is phenylsubstituted with one to three groups independently selected from R³. Ina subclass of this class, R² is phenyl substituted with two groupsindependently selected from R³. In a subclass of this subclass, R² isphenyl substituted with two halogen groups.

In a third embodiment of the compounds of structural formula I and II, Xis selected from the group consisting of: (CH₂)_(n)-phenyl,(CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)C₃₋₈ cycloalkyl, and(CH₂)_(n)-heterocyclyl, wherein heteroaryl is as defined above, andphenyl, naphthyl, and heteroaryl are optionally substituted with one tothree groups independently selected from R⁶; cycloalkyl and heterocyclylare optionally substituted with one to three groups independentlyselected from R⁶ and oxo; and wherein any methylene (CH₂) group in X isunsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl. In a class of thisembodiment, X is selected from the group consisting of (CH₂)₀₋₁-phenyl,(CH₂)₀₋₁-heteroaryl, (CH₂)₀₋₁-heterocyclyl; wherein phenyl andheteroaryl are optionally substituted with one to three groupsindependently selected from R⁶; heterocyclyl is optionally substitutedwith one to three groups independently selected from R⁶ and oxo; and CH₂is unsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl. In a subclass of thisclass, X is phenyl optionally substituted with one to three groupsindependently selected from R⁶.

In a fourth embodiment of compounds of formula I and II, Y is hydrogen.

In yet a further embodiment of compounds of structural formula I and II,r is 1 or 2 and s is 1.

A specific melanocortin-4 receptor agonist useful in the methods of thepresent invention is Compound A:

Compound A is a selective agonist for MC4R, with a selective functionalactivity characterized by an EC₅₀ value for the melanocortin 4 receptorthat is at least 120-fold lower than for the melanocortin 1 receptor, atleast 700-fold lower than for the melanocortin 2 receptor, at least65-fold lower than for the melanocortin 3 receptor, and at least 100fold lower than for the melanocortin 5 receptor.

Other melanocortin-4 receptor agonists useful in the methods of thepresent invention include, but are not limited to, the following:

or a pharmaceutically acceptable salt thereof.

The melanocortin 4 receptor agonists of Formula I and II, includingCompound A, and their preparation are disclosed in US2003/0225060, whichis hereby incorporated by reference in its entirety, WO 02/068387, andWO 02/068388.

The above compounds are only illustrative of the non-peptidyl MC4Ragonists that can be used in the compositions of the present invention.As this listing of compounds is not meant to be comprehensive, themethods of the present invention may employ any non-peptidyl MC4Ragonists, including the MC4R agonists of Formulas I, II, and Compound A,and are not limited to any particular structural class of compounds.

Other melanocortin 4 receptor agonists useful in the present invention,include but are not limited to those disclosed in U.S. Pat. No.6,294,534, U.S. Pat. Nos. 6,350,760, 6,376,509, 6,410,548, 6,458,790,U.S. Pat. No. 6,472,398, U.S. Pat. No. 5,837,521, U.S. Pat. No.6,699,873, which are hereby incorporated by reference in their entirety;in US Patent Application Publication Nos. US 2002/0004512,US2002/0019523, US2002/0137664, US2003/0236262, US2003/0225060,US2003/0092732, US2003/109556, US 2002/0177151, US 2002/187932, US2003/0113263, which are hereby incorporated by reference in theirentirety; and in WO 99/64002, WO 00/74679, WO 02/15909, WO 01/70708, WO01/70337, WO 01/91752, WO 02/068387, WO 02/068388, WO 02/067869, WO03/007949, WO 2004/024720, WO 2004/037797, WO 04/078717, WO 04/087159,WO 04/089307, WO 05/009950, WO 01/58891, WO 02/070511, WO 02/079146, WO03/009847, WO 03/057671, WO 03/068738, WO 03/092690, WO 02/059095, WO02/059107, WO 02/059108, WO 02/059117, WO 02/085925, WO 03/004480, WO03/009850, WO 03/013571, WO 03/031410, WO 03/053927, WO 03/061660, WO03/066597, WO 03/094918, WO 03/099818, WO 04/037797, WO 04/048345, WO04/058735, WO 02/018327, WO 02/080896, WO 02/081443, WO 03/066587, WO03/066597, WO 03/099818, WO 02/062766, WO 03/000663, WO 03/000666, WO03/003977, WO 03/040107, WO 03/040117, WO 03/040118, WO 03/013509, WO03/057671, WO 02/079753, WO 02//092566, WO 03/-093234, WO 03/095474 andWO 03/104761.

One of ordinary skill in the art can readily identify melanocortin 4receptor agonist compounds useful in the compositions and methods of thepresent invention using the methods described in Example 1. MC4Ragonists which are useful in the present invention generally have anIC₅₀ less than 100 nM in the MC4R agonist binding assay and an EC₅₀ lessthan 100 nM in the functional assay described in Example 2. Particularlyuseful in the present invention are MC4R agonists with an IC₅₀ less than45 nM or an EC₅₀ less than 15 nM. More particularly useful in thepresent in invention are MC4R agonists with an EC₅₀ less than 15 nM andan IC₅₀ less than 45 nM.

Throughout the instant application, the following terms have theindicated meanings:

The alkyl groups specified above are intended to include those alkylgroups of the designated length in either a straight or branchedconfiguration. Exemplary of such alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl,isohexyl, and the like.

The term “halogen” is intended to include the halogen atoms fluorine,chlorine, bromine and iodine.

The term “C₁₋₄ alkyliminoyl” means C₁₋₃C(═NH)—.

The term “aryl” includes phenyl and naphthyl.

The term “heteroaryl” includes mono- and bicyclic aromatic ringscontaining from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur. “5- or 6-Membered heteroaryl” represents a monocyclicheteroaromatic ring; examples thereof include thiazole, oxazole,thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole,thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine,pyrazine, and the like. Bicyclic heteroaromatic rings include, but arenot limited to, benzothiadiazole, indole, benzothiophene, benzofuran,benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole,benzoxazole, isoquinoline, purine, furopyridine and thienopyridine.

The term “5- or 6-membered carbocyclyl” is intended to includenon-aromatic rings containing only carbon atoms such as cyclopentyl andcyclohexyl.

The term “5 and 6-membered heterocyclyl” is intended to includenon-aromatic heterocycles containing one to four heteroatoms selectedfrom nitrogen, oxygen and sulfur. Examples of a 5 or 6-memberedheterocyclyl include piperidine, morpholine, thiamorpholine,pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other; thus for example, NR⁴R⁴ may represent NH₂,NHCH₃, N(CH₃)CH₂CH₃, and the like.

It will be understood that, as used herein, references to MC4R agonists,including MC4R agonists of Formulas I and II, and compound A, are meantto also include the pharmaceutically acceptable salts and estersthereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, lithium, magnesium, potassium, and sodium salts.Salts derived from pharmaceutically acceptable organic nontoxic basesinclude salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines,and basic ion exchange resins, such as arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric,pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric,tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like.Particularly preferred are citric, fumaric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids. It will be understoodthat, as used herein, references to the compounds of Formula I, formulaII, compound A, and other melanocortin 4 receptor agonists, are meant toalso include the pharmaceutically acceptable salts, such as thehydrochloride salts.

The compounds useful in the methods of the present invention includestereoisomers, such as optical isomers, diastereomers and geometericalisomers, or tautomers depending on the mode of substitution. Thecompounds may contain one or more chiral centers and occur as racemates,racemic mixtures and as individual diastereomers, enantiomeric mixturesor single enantiomers, keto-enol tautomers, or E and Z olefinicgeometric isomers, with all isomeric forms being included in the presentinvention. The present invention is meant to comprehend all suchisomeric forms of the compounds in the compositions of the presentinvention, and their mixtures. Therefore, where a compound is chiral,the separate enantiomers, substantially free of the other, are includedwithin the scope of the invention; further included are all mixtures ofthe two enantiomers. Also included within the scope of the invention arepolymorphs, hydrates and solvates of the compounds of the instantinvention.

The present invention includes within its scope prodrugs of thecompounds in the compositions of this invention. In general, suchprodrugs will be functional derivatives of the compounds in thesecompositions which are readily convertible in vivo into the requiredcompound. Thus, in the methods of treatment of the present invention,the term “administering” shall encompass the treatment of alcoholism,alcohol abuse, alcohol consumption and alcohol related disorders withthe compounds specifically disclosed as elements of the composition orwith compounds which may not be specifically disclosed, but whichconvert to the specified compounds in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs,” ed. H. Bundgaard, Elsevier, 1985.

Utility

The compounds of the present invention are useful to inhibit or reducevoluntary alcohol consumption, and for the treatment or prevention ofalcoholism, alcohol abuse, and alcohol-related disorders.

Alcoholism, also known as alcohol dependence, is a disease that ischaracterized by abnormal alcohol seeking behavior that leads toimpaired control over drinking. Alcoholism may include some or all ofthe following symptoms: narrowing of drinking repertoire (drinking onlyone brand or type of alcoholic beverage); craving (a strong need or urgeto drink), loss of control (not being able to stop drinking oncedrinking has begun), drink seeking behavior (attending only socialevents that include drinking); physical dependence (withdrawal symptoms,such as nausea, sweating, shakiness, and anxiety after cessation ofdrinking), drinking to relieve or avoid withdrawal symptoms; andtolerance (the need to drink greater amounts of alcohol to achieveprevious effects); subjective awareness of the compulsion to drink orcraving for alcohol; and relapse (a return to drinking after a period ofabstinence).

Alcohol abuse is a pattern of drinking that results in one or more ofthe following situations within a 12 month period: failure to fulfillmajor work, school or home responsibilities; drinking in situations thatare physically dangerous, such as while driving a car or operatingmachinery; having recurring alcohol related legal problems, such asbeing arrested for driving under the influence of alcohol, or physicallyhurting someone while drunk; and continued drinking despite ongoingrelationship problems that are caused or worsened by the drinking.Harmful alcohol use implies alcohol use that causes health consequences,such as physical or mental damage. Alcohol related disorders include,but are not limited to, disorders resulting from alcohol dependence,alcohol abuse and alcohol consumption. Alcohol related disordersinclude, but are not limited to: liver disease, such as hepatitis,inflammation of the liver, and alcoholic cirrhosis; heart disease; highblood pressure; stroke; certain forms of cancer, such as esophageal,mouth, throat, voice box, breast, colon and rectal cancer; pancreatitis;alcoholic dementia, Wernicke-Korsakoff syndrome, brain damage, slow bonehealing; impaired wound healing; diminished immune defenses; and death.Alcohol misuse has also been found to predispose the subject toosteoporosis, slow bone healing, impaired wound healing, inhibitedosteoblastic function and diminished immune defenses. Alcoholintoxication increases the risk of further accidents, and decreases thepain inhibition that would make a normal patient more careful. Alcoholdependence also leads to altered cognitive and emotional functions, andthought processes, such as impaired judgment, feelings of incompetency,low self-esteem, despair in relationships, depression, and feelings offailure.

“Treatment” (of alcoholism or alcohol abuse) refers to theadministration of the compounds or combinations of the present inventionto reduce or inhibit the consumption of alcohol in a subject. Oneoutcome of treatment may be reducing the consumption of alcohol in asubject relative to the subject's alcohol consumption prior totreatment. Another outcome of treatment may be inhibiting consumption ofalcohol in a subject. Another outcome of treatment may be decreasing theoccurrence of alcohol intake in a subject. Another outcome of treatmentmay be decreasing the severity of alcohol intake, such as decreasing theamount of alcohol consumed, in a subject. Another outcome of treatmentmay be to administer the compounds or combinations of the presentinvention to reduce or inhibit the consumption of alcohol in a subjectin need thereof.

The term “inhibit” alcohol consumption means to stop alcohol consumptionin a subject. One outcome of inhibition may be to stop alcoholconsumption in a subject in need thereof.

The term “reduce” alcohol consumption means to decrease the amount ofalcohol consumed by a subject relative to the amount of alcohol consumedprior to the start of treatment. In one embodiment the amount of alcoholconsumed by a subject is decreased by at least 10% relative to theamount of alcohol consumed prior to the start of treatment. In anotherembodiment, the amount of alcohol consumed by a subject is decreased byat least 25% relative to the amount of alcohol consumed prior to thestart of treatment. In another embodiment, the amount of alcoholconsumed by a subject is decreased by at least 67% relative to theamount of alcohol consumed prior to the start of treatment. In yetanother embodiment, the amount of alcohol consumed by a subject isdecreased by at least 86% relative to the amount of alcohol consumedprior to the start of treatment.

“Prevention” (of alcoholism) refers to the administration of thecompounds or combinations of the present invention to prevent alcoholintake, alcohol consumption, alcohol abuse, alcoholism or developing analcohol-related disorder in a subject by administration prior to thestart of alcohol consumption. One outcome of prevention may be toprevent alcohol intake in a subject by administration prior to the startof alcohol consumption. Another outcome of prevention may be to preventalcohol abuse in a subject. Another outcome of prevention may be toprevent alcoholism in a subject. Another outcome of prevention may be toprevent the development of an alcohol-related disorder in a subject.Another outcome of prevention may be preventing alcohol consumption fromoccurring if the treatment is administered prior to the onset of alcoholconsumption in a subject. Another outcome of prevention may be toprolong resistance to alcohol consumption in a subject. Another outcomeof prevention may be to administer the compounds or combinations of thepresent invention to prevent alcohol intake in a subject at risk ofalcohol consumption, alcohol abuse, alcoholism or developing analcohol-related disorder in a subject.

Moreover, if treatment is commenced in a subject already consumingalcohol, such treatment may prevent the occurrence, progression orseverity of alcohol-related disorders, such as, but not limited to,liver disease; hepatitis; inflammation of the liver; alcoholiccirrhosis; heart disease; high blood pressure; stroke; esophagealcancer, mouth cancer; throat cancer; voice box cancer; breast cancer;colon cancer; rectal cancer; pancreatitis; alcoholic dementia;Wernicke-Korsakoff syndrome; brain damage; osteoporosis; slow bonehealing; impaired wound healing; diminished immune defenses; depression;and death.

The term “alcohol” is understood to mean ethanol.

The term “selective” means having an activation preference for aspecific receptor over other receptors which can be quantified basedupon whole cell, tissue, or organism assays which demonstrate receptoractivity, such as the cAMP Functional Assay and the Binding AffinityAssay. The compounds of the present invention interact preferentially(i.e. selectively) with the MC-4 receptor relative to the othermelanocortin receptors. Selectivity for the MC-4 receptor is beneficialfor compounds administered to humans or mammals, to minimize the numberof side effects associated with their administration. MC-4 selectivityof a compound over another MC receptor is defined herein as the EC₅₀, orIC₅₀, of the compound at the MC receptor being referenced over the EC₅₀,or IC₅₀, of the compound for the MC-4 receptor. As used herein, unlessindicated otherwise, use of the term “selective over the other MCreceptors” means selective with respect to the other melanocortinreceptors, including the MC-1, MC-2, MC-3 and MC-5 receptors. Forexample, a compound having an EC₅₀ of 8 nM at the MC-4 receptor and anEC₅₀ of >80 nM at the MC-1, MC-2 MC-3, and MC-5 receptors has aselectivity ratio for the MC-4 receptor over the other MC receptors ofat least 1:10. Additionally, the term “selective” may also refer to oneof the MC-1, MC-2, MC-3 or MC-5 receptors individually. For example, acompound having an EC₅₀ of 8 nM at the MC-4 receptor and an EC₅₀ of 80nM at the MC-1 receptor has a selectivity ratio for the MC-4 receptorover the MC-1 receptor of 1:10. Such a compound is selective over theMC-1 receptor regardless of its EC₅₀ value for the MC-2R or MC-5R. Forexample, the selectivity of a compound for the MC-4R over the MC-1R isdefined as: MC-4R functional selectivity, EC₅₀=[EC₅₀ MC-1R]/[EC₅₀MC-4R], or MC-4R binding selectivity, IC₅₀=[IC₅₀ MC-1R]/[IC₅₀ MC-4R]. Acompound is defined herein as being “selective” for the MC-4 receptorwhen the above mentioned ratio is at least 10, preferably at least 65,and more preferably at least about 100.

The terms “administration of” and or “administering” a compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to a subject. The instant pharmaceuticalcomposition includes administration of a single pharmaceutical dosageformulation which contains the melanocortin 4 receptor agonist.

The term “subject”, as used herein refers to an animal, preferably amammal, more preferably a human. In one embodiment of the presentinvention, the term “subject” refers to a human that is or has been theobject of treatment, observation or experiment. In another embodiment ofthe present invention, the term “subject” refers to a “subject in needthereof”. In a class of this embodiment, the “subject in need thereof”refers to a subject who is in need of treatment or prophylaxis asdetermined by a researcher, veterinarian, medical doctor or otherclinician. In another embodiment, the “subject in need thereof” is ahuman that is alcohol dependent. In another embodiment, the “subject inneed thereof” is a human that is an alcoholic. In another embodiment,the “subject in need thereof” is a human that abuses alcohol. In anotherembodiment, the “subject in need thereof” is a human that consumesalcohol. In another embodiment, the “subject in need thereof” has analcohol-related disorder. In another embodiment, the “subject in needthereof” is a subject experiencing the alcohol deprivation effect. Inyet another embodiment of the present invention, the term “subject”refers to a “subject at risk thereof”. In a class of this embodiment,the “subject at risk thereof” is a subject at risk of developingalcoholism. In another class of this embodiment, the “subject at riskthereof” is a subject at risk of developing an alcohol-related disorder.In another embodiment, the “subject in need thereof” is at risk ofexperiencing the alcohol deprivation effect. An embodiment of the term“mammal in need thereof” is a “human in need thereof,” said human beingeither male or female.

The term “a subject currently consuming alcohol” as used herein refersto a subject that has not undergone alcohol detoxification and has notachieved alcohol abstinence at the time of treatment initiation.

The administration of the composition of the present invention in orderto practice the present methods of therapy is carried out byadministering a therapeutically effective amount of the compounds in thecomposition to a subject in need of such treatment or prophylaxis. Theneed for a prophylactic administration according to the methods of thepresent invention is determined via the use of well known risk factors.The effective amount of an individual compound is determined, in thefinal analysis, by the physician in charge of the case, but depends onfactors such as the exact disease to be treated, the severity of thedisease and other diseases or conditions from which the patient suffers,the chosen route of administration, other drugs and treatments which thepatient may concomitantly require, and other factors in the physician'sjudgment.

The term “therapeutically effective amount” as used herein means theamount of the active compounds in the composition that will elicit thebiological or medical response in a tissue, system, subject, or humanthat is being sought by the researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisorder being treated. Disorders being treated include, but are notlimited to, alcohol dependence, alcoholism, or alcohol abuse, or alcoholconsumption or an alcohol-related disorder in subjects in need thereof.The novel methods of treatment of this invention are for disorders knownto those skilled in the art.

The term “prophylactically effective amount” as used herein means theamount of the active compounds that will elicit the biological ormedical response in a tissue, system, subject, or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, to prevent the onset of alcohol dependence, alcoholism, oralcohol abuse, or alcohol consumption or an alcohol-related disorder insubjects as risk for alcohol dependence, alcoholism, alcohol abuse,alcohol consumption or an alcohol-related disorder.

The term “alcohol deprivation effect” as used herein means the transientincrease in oral ethanol self administration following forceddeprivation of alcohol consumption, or abstinence from alcoholconsumption after a period of alcohol consumption, and is characterizedby loss of control over intake.

The term “composition”, as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

By a melanocortin receptor “agonist” is meant an endogenous or drugsubstance or compound that can interact with a melanocortin receptor andinitiate a pharmacological response characteristic of the melanocortinreceptor. By a melanocortin receptor “antagonist” is meant a drug or acompound that opposes the melanocortin receptor-associated responsesnormally induced by another bioactive agent. The “agonistic” propertiesof the compounds of the present invention were measured in thefunctional assay described below. The functional assay discriminates amelanocortin receptor agonist from a melanocortin receptor antagonist.

By “binding affinity” and “binding affinity index” is meant the abilityof a compound/drug to bind to its biological target, in the presentinstance, the ability of a melanocortin 4 receptor agonist, includingcompounds of structural formula I and II, to bind to a melanocortinreceptor. Binding affinities for the compounds of the present inventionwere measured in the binding assay described below and are expressed asIC₅₀ values.

“Efficacy” describes the relative intensity with which agonists vary inthe response they produce even when they occupy the same number ofreceptors and with the same affinity. Efficacy is the property thatenables drugs to produce responses. Properties of compounds/drugs can becategorized into two groups, those which cause them to associate withthe receptors (binding affinity) and those that produce a stimulus(efficacy). The term “efficacy” is used to characterize the level ofmaximal responses induced by agonists. Not all agonists of a receptorare capable of inducing identical levels of maximal responses. Maximalresponse depends on the efficiency of receptor coupling, that is, fromthe cascade of events, which, from the binding of the drug to thereceptor, leads to the desired biological effect.

The functional activities expressed as EC₅₀'s and the “agonist efficacy”for the compounds of the present invention at a particular concentrationwere measured in the functional assay described below.

The magnitude of prophylactic or therapeutic dose of the activeingredient (the MC4R agonist) will, of course, vary with the nature ofthe severity of the condition to be treated and with the particularcompound and its route of administration. It will also vary according tothe age, weight and response of the individual patient. In general, thedaily dose range of each compound lies within the range of from about0.001 mg/kg to about 1000 mg/kg; more specifically from about 0.001mg/kg to about 100 mg/kg body weight of a subject per day in single ordivided doses. On the other hand, it may be necessary to use dosagesoutside these limits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.001 mg/kg to about 1000 mg/kg;more specifically from 0.001 mg/kg to about 100 mg/kg of each compoundin the composition per day.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.001 mg/kg to about 1000 mg/kg of eachcompound in the composition per day; more specifically from about 0.001mg/kg to about 100 mg/kg per day. For oral administration, thecompositions are provided in the form of tablets containing from 0.01 mgto 1,000 mg; more specifically 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5,10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500,650, 750, 850 and 1,000 milligrams of each active ingredient for thesymptomatic adjustment of the dosage to the subject to be treated. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse.

The compounds of this invention can be administered to humans in thedosage ranges specific for each compound. In general, for treatingalcoholism, alcohol abuse, alcohol consumption and/or an alcohol relateddisorder, the MC4R agonist is administered at a daily dosage of fromabout 0.001 mg/kg to about 1000 mg/kg of body weight orally. Morespecifically, when treating alcoholism, alcohol abuse, alcoholconsumption and/or an alcohol related disorder, generally satisfactoryresults may be obtained when a MC4R agonist, such as a MC4R agonist ofFormula I, Formula II and Compound A, or a pharmaceutically acceptablesalt or ester thereof, is administered at a daily oral dosage of fromabout 0.001 mg/kg to about 1000 mg/kg; more specifically from about0.001 mg/kg to about 100 mg/kg of body weight, given in a single dose orin divided doses two to six times a day, or in sustained release form.In the case of a 70 kg adult human, the total daily dose will generallybe from about 0.07 milligrams to about 3500 milligrams.

The effective dosage of the active ingredient employed in thecomposition may vary depending on the particular compound employed, themode of administration, the condition being treated and the severity ofthe condition being treated. Thus, the dosage regimen utilizing thecompositions of the present invention is selected in accordance with avariety of factors including type, species, age, general health, bodyweight, diet, sex and medical condition of the subject; the severity ofthe condition to be treated; the renal and hepatic function of thepatient; the drug combination; and the particular compound employed andits route of administration. A physician, clinician or veterinarian ofordinary skill can readily determine and prescribe the effective amountof the drug required to prevent, counter or arrest the progress of thecondition.

Combination Therapy

The melanocortin 4 receptor agonists useful in the methods of thepresent invention may be used in combination with other drugs that areused in the treatment or prevention of alcoholism, alcohol abuse,alcohol consumption and/or an alcohol related disorder. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a melanocortin 4 receptoragonist. When a melanocortin 4 receptor agonist is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the melanocortin4 receptor agonist is preferred. Accordingly, the pharmaceuticalcompositions useful in the methods of the present invention includethose that also contain one or more other active ingredients, inaddition to a melanocortin 4 receptor agonist.

Examples of other active ingredients that may be combined with themelanocortin 4 receptor agonists useful in the present invention for thetreatment or prevention of alcoholism, alcohol abuse, alcoholconsumption and/or an alcohol related disorder, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to:

(a) cannabinoid CB-1 antagonists/inverse agonists, such as rimonabant;

(b) bupropion;

(c) opioid antagonists, such as naloxone, naltrexone, and nalmefene;

(d) inhibitors of acetaldehye metabolism, such as disulfuram;

(e) dopamine D3 antagonists/inverse agonists; and

(f) GABA agonists such as acamprosate.

Additionally, the use of combination therapy in the methods of thepresent invention, comprising administering a therapeutically effectiveamount of a melanocortin 4 receptor agonist with a therapeuticallyeffective or subtherapeutically effective amount, of a medicationapproved to inhibit alcohol consumption, that acts via a differentcomplementary mechanism, will result in improved efficacy.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions useful for the methods of the present invention comprisinga pharmaceutical carrier and a therapeutically effective amount of amelanocortin-4 receptor agonist and each additional compound in thecomposition of the present invention. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s), suchas pharmaceutically acceptable excipients, that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a melanocortin 4receptor agonist, additional active ingredient(s), and/orpharmaceutically acceptable excipients and carriers.

Any suitable route of administration may be employed for providing asubject, especially a human, with an effective dosage of a compositionof the present invention. For example, oral delivery, rectal delivery,topical delivery, parenteral delivery, ocular delivery, pulmonarydelivery, nasal delivery, delivery to the central nervous system, inparticular the brain, and the like may be employed. Dosage forms includetablets, troches, dispersions, suspensions, solutions, capsules, creams,ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise a MC4Ragonist, as active ingredient or a pharmaceutically acceptable salt orester thereof, and may also contain a pharmaceutically acceptablecarrier and optionally other therapeutic ingredients. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. In particular,the term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic bases or acids and organic bases or acids.

The compositions include compounds suitable for oral, rectal, topical,parenteral (including subcutaneous, intramuscular, and intravenous),ocular (ophthalmic), pulmonary (aerosol inhalation), or nasaladministration, although the most suitable route in any given case willdepend on the nature and severity of the conditions being treated and onthe nature of the active ingredient. These compositions may beconveniently presented in unit dosage form and prepared by any of themethods well-known in the art of pharmacy.

For administration by inhalation, the compositions of the presentinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or nebulizers. The compositions mayalso be delivered as powders which may be formulated and the powdercomposition may be inhaled with the aid of an insufflation powderinhaler device. The preferred delivery systems for inhalation aremetered dose inhalation (MDI) aerosol, which may be formulated as asuspension or solution of the instant composition in suitablepropellants, such as fluorocarbons or hydrocarbons and dry powderinhalation (DPI) aerosol, which may be formulated as a dry powder of thecomposition with or without additional excipients. Suitable topicalformulations of the compositions of the present invention includetransdermal devices, aerosols, creams, solutions, ointments, gels,lotions, dusting powders, and the like. The topical pharmaceuticalcompositions containing the compositions of the present inventionordinarily include about 0.005% to 5% by weight of the active compoundsin admixture with a pharmaceutically acceptable vehicle. Transdermalskin patches useful for administering the compositions of the presentinvention include those well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course be continuous rather thanintermittent throughout the dosage regimen. The compositions of thepresent invention can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, sterylamine orphosphatidylcholines. Compositions of the present invention may also bedelivered by the use of monoclonal antibodies as individual carriers towhich the compound molecules are coupled. The compounds in thesecompositions may also be coupled with soluble polymers as targetabledrug carriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropyl-methacrylamide phenol,polyhydroxyethylasparamidepheon, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compositions ofthe present invention may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

In practical use, each compound in the compositions of the presentinvention (e.g. MC4R agonist) can be combined as the active ingredientin intimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending on the form of preparation desired foradministration, e.g., oral or parenteral (including intravenous). Inpreparing the compositions for oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like in the case of oral liquid preparations, such as,for example, suspensions, elixirs and solutions; or carriers such asstarches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like in thecase of oral solid preparations such as, for example, powders, capsules,pellet, powder and tablets, with the solid oral preparations beingpreferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compositionmay also be administered by controlled release means and/or deliverydevices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; 3,630,200 and 4,008,719, which are herebyincorporated by reference in their entirety.

For example, for oral administration in the form of a tablet, capsule,pellet, or powder, the active ingredient can be combined with an oral,non-toxic, pharmaceutically acceptable inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, croscarmellose sodium and the like; for oraladministration in liquid form, e.g., elixirs, syrups, slurries,emulsions, suspensions, solutions, and effervescent compositions, theoral drug components can be combined with any oral, non-toxic,pharmaceutically acceptable inert carrier such as ethanol, glycerol,water, oils and the like. Moreover, when desired or necessary, suitablebinders, lubricants, disintegrating agents, buffers, coatings, andcoloring agents can also be incorporated. Suitable binders can includestarch, gelatin, natural sugars such a glucose, anhydrous lactose,free-flow lactose, beta-lactose, and corn sweeteners, natural andsynthetic gums, such as acacia, guar, tragacanth or sodium alginate,carboxymethyl cellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Various other materials may be present ascoatings or to modify the physical form of the dosage unit. Forinstance, tablets may be coated with shellac, sugar or both. A syrup orelixir may contain, in addition to the active ingredient, sucrose as asweetening agent, methyl and propylparabens as preservatives, a dye anda flavoring such as cherry or orange flavor. When a dosage unit form isa capsule, it may contain, in addition to materials of the above type, aliquid carrier such as a fatty oil. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

Desirably, each tablet contains from 0.01 to 1,000 mg, particularly0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75,100, 125, 150, 175, 200, 225, 250, 500, 600, 750, 850 and 1,000milligrams of each active ingredient in the composition of the presentinvention (e.g. MC4R agonist) for the symptomatic adjustment of thedosage to the subject to be treated; and each cachet or capsule containsfrom about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.2, 0.5,1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200,225, 250, 500, 600, 750, 850 and 1,000 milligrams of each active in thecomposition of the present invention (e.g. MC4R agonist) for thesymptomatic adjustment of the dosage to the subject to be treated.

Exemplifying the invention is a pharmaceutical composition comprising aMC4R agonist described above and a pharmaceutically acceptable carrier.Also exemplifying the invention is a pharmaceutical composition made bycombining any of the MC4R agonists described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the MC4R agonists described above and a pharmaceuticallyacceptable carrier.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two to six times daily.Furthermore, based on the properties of the individual compound selectedfor administration, the dose may be administered less frequently, e.g.,weekly, twice weekly, monthly, etc. The unit dosage will, of course, becorrespondingly larger for the less frequent administration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage formsfor the compositions of the present invention: Tablet mg/tablet CompoundA 25 Microcrystalline Cellulose 50.5 Lactose 111.5 Croscarmellose Sodium5.0 Hydroxypropylcellulose 6.0 Sodium Dodecyl Sulfate 1.0 MagnesiumStearate 1.0 200 Capsule mg/capsule Compound A 100 Lactose 80 SodiumDodecyl Sulfate 20 200 Aerosol Per canister Compound A 13 mg Lecithin,NF Liq. Conc. 1.2 mg Trichlorofluoromethane, NF 4.65 gDichlorodifluoromethane, NF 12.15 g 30Combination Therapy

It will be understood that the scope of compositions of the compounds ofthis invention with other agents useful to inhibit or reduce alcoholconsumption and for treating or preventing alcoholism, alcohol abuse,and alcohol related conditions includes in principle any combinationwith any pharmaceutical composition useful to inhibit or reduce alcoholconsumption and for treating alcoholism, alcohol abuse and alcoholrelated disorders.

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of reducing the invention to practice. Those skilledin the art may find other methods of practicing the invention which arereadily apparent to them. However, those methods are also deemed to bewithin the scope of this invention.

EXAMPLE 1 Binding Assay

The membrane binding assay was used to identify competitive inhibitorsof ¹²⁵I-NDP-alpha-MSH binding to cloned human MCRs expressed in mouse L-or Chinese hamster ovary (CHO)-cells.

Cell lines expressing melanocortin receptors were grown in T-180 flaskscontaining selective medium of the composition: 1 L Dulbecco's modifiedEagles Medium (DMEM) with 4.5 g L-glucose, 25 mM Hepes, without sodiumpyruvate, (Gibco/BR1); 100 ml 10% heat-inactivated fetal bovine serum(Sigma); 10 mL 10,000 unit/mL penicillin & 10,000 μg/mL streptomycin(Gibco/BR1); 10 ml 200 mM L-glutamine (Gibco/BR1); 1 mg/mL geneticin(G418) (Gibco/BR1). The cells were grown at 37° C. with CO₂ and humiditycontrol until the desired cell density and cell number was obtained.

The medium was poured off and 10 mls/T-180 flask of enzyme-freedissociation media (Specialty Media Inc.) was added. The cells wereincubated at 37° C. for 10 min or until cells sloughed off when flaskwas banged against hand.

The cells were harvested into 200 mL centrifuge tubes and spun at 1000rpm, 4° C., for 10 min. The supernatant was discarded and the cells wereresuspended in 5 mls/monolayer membrane preparation buffer having thecomposition: 10 mM Tris pH 7.2-7.4; 4 μg/mL Leupeptin (Sigma); 10 μMPhosphoramidon (Boehringer Mannheim); 40 μg/mL Bacitracin (Sigma); 5μg/mL Aprotinin (Sigma); 10 mM Pefabloc (Boehringer Mannheim). The cellswere homogenized with motor-driven dounce (Talboy setting 40), using 10strokes and the homogenate centrifuged at 6,000 rpm, 4° C., for 15 min.

The pellets were resuspended in 0.2 mls/monolayer membrane prep bufferand aliquots were placed in tubes (500-1000 μL/tube) and quick frozen inliquid nitrogen and then stored at −80° C.

Test compounds or unlabelled NDP-α-MSH was added to 100 μL of membranebinding buffer to a final concentration of 1 μM. The membrane bindingbuffer had the composition: 50 mM Tris pH 7.2; 2 mM CaCl₂; 1 mM MgCl₂; 5mM KCl; 0.2% BSA; 4 μg/mL Leupeptin (SIGMA); 10 μM Phosphoramidon(Boehringer Mannheim); 40 μg/mL Bacitracin (SIGMA); 5 μg/mL Aprotinin(SIGMA); and 10 mM Pefabloc (Boehringer Mannheim). One hundred [L ofmembrane binding buffer containing 10-40 μg membrane protein was added,followed by 100 μM 125]-NDP-α-MSH to final concentration of 100 μM. Theresulting mixture was vortexed briefly and incubated for 90-120 min atroom temp while shaking.

The mixture was filtered with Packard Microplate 196 filter apparatususing Packard Unifilter 96-well GF/C filter with 0.1% polyethyleneimine(Sigma). The filter was washed (5 times with a total of 10 mL per well)with room temperature of filter wash having the composition: 50 mMTris-HCl pH 7.2 and 20 mM NaCl. The filter was dried, and the bottomsealed and 50 μL of Packard Microscint-20 was added to each well. Thetop was sealed and the radioactivity quantitated in a Packard TopcountMicroplate Scintillation counter.

Melanocortin-4 receptor agonists of use in the present invention arecompounds which are potent melanocortin-4 receptor agonists, i.e.compounds with an MC4R affinity (IC₅₀) of less than 300 nM, preferablyless than 100 nM, and more preferably less than 45 nM.

Results of binding assay (Example 1) and selectivity for representativecompounds of the present invention are provided below: IC₅₀ (nM) BindingAssay IC₅₀ (nM) Selectivity Binding IC₅₀ Compound hMC4R hMC1bR hMC3RhMC5R 1R/4R 3R/4R 5R/4R A 44 5600 7200 1600 127.27 163.6 36.36 B 3477600 >20000 5250 21.90 >57.64 >15.13 C 420 >20000 3900 >47.62 >9.29 D182 >20000 4600 >109.89 >25.27 E 520 >20000 6300 >38.46 >12.12

EXAMPLE 2 cAMP Functional Assay To Discriminate Melanocortin ReceptorAgonists from Antagonists

Cells (for example, CHO- or L-cells or other eukaryotic cells)expressing a human melanocortin receptor (see e.g. Yang-YK; Ollmann-MM;Wilson-BD; Dickinson-C; Yamada-T; Barsh-GS; Gantz-I; Mol-Endocrinol.1997 March; 11(3): 274-80) were dissociated from tissue culture flasksby rinsing with Ca and Mg free phosphate buffered saline (14190-136,Life Technologies, Gaithersburg, Md.) and detached following 5 minincubation at 37° C. with enzyme free dissociation buffer (S-014-B,Specialty Media, Lavellette, N.J.). Cells were collected bycentrifugation and resuspended in Earle's Balanced Salt Solution(14015-069, Life Technologies, Gaithersburg, Md.) with additions of 10mM HEPES pH 7.5, 5 mM MgCl₂, 1 mM glutamine and 1 mg/ml bovine serumalbumin. Cells were counted and diluted to 1 to 5×10⁶/mL. Thephosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was added tocells to 0.6 mM.

Agonist Assay: Test compounds were diluted in dimethylsulfoxide (DMSO)(10⁻⁵ to 10⁻¹⁰ M) and 0.1 volume of compound solution was added to 0.9volumes of cell suspension; the final DMSO concentration was 1%. Afterroom temperature incubation for 45 min, cells were lysed by incubationat 100° C. for 5 min to release accumulated cAMP.

cAMP was measured in an aliquot of the cell lysate with the Amersham(Arlington Heights, Ill.) cAMP detection assay (RPA556). The amount ofcAMP production which resulted from an unknown compound was compared tothat amount of cAMP produced in response to alpha-MSH which was definedas a 100% agonist. The EC₅₀ is defined as the compound concentrationwhich results in half maximal stimulation, when compared to its ownmaximal level of stimulation.

Antagonist assay: Antagonist activity was defined as the ability of acompound to block cAMP production in response to alpha-MSH or otheragonists. Solution of test compounds and suspension of receptorcontaining cells were prepared and mixed as described above; the mixturewas incubated for 15 min, and an EC₅₀ dose (approximately 10 nMalpha-MSH) was added to the cells. The assay was terminated at 45 minand cAMP quantitated as above. Percent inhibition was determined bycomparing the amount of cAMP produced in the presence to that producedin the absence of test compound.

Melanocortin-4 receptor agonists of use in the present invention arecompounds which are potent melanocortin-4 receptor agonists, i.e.compounds with an MC4R functional activity (EC₅₀) less than 90 nM,preferably less than 40 nM, and more preferably less than 15 nM.

Results of cAMP assay (Example 2) and selectivity for representativecompounds of the present invention are provided below: EC50 (nM) cAMPAssay EC50 (nM) Selectivity cAMP EC50 Compound hMC4R hMC1bR hMC2R hMC3RhMC5R 1R/4R 2R/4R 3R/4R 5R/4R A 14 1700 >10000 920 1400 121.43 >714.265.71 100 B 88 1804 2967 >5000 20.50 33.72 >56.8 C 76 1100 2625 >500014.47 34.54 >65.7 D 27 580 1500 3600 21.48 55.56 133.3 E 1201800 >5000 >5000 15.00 41.67 41.67

EXAMPLE 3 Maintenance Ethanol Self-Administration Following Treatment ofMC4R Agonist (Compound A)

Animals: Male Wistar rats were used in all experiments. Body weight was180-200 g at the start of the experiments. Rats were housed 2-3 per cagewith food and water available ad libitum. Lights were on a 12-hourlight/dark cycle, with lights on at 0600. All procedures met theguidelines of the National Institutes of Health Guide for the Care andUse of Laboratory Animals.

Operant Ethanol Self-Administration: Ethanol dilutions (5, 8 and 10%w/v) were prepared with 95% ethyl alcohol and tap water. Saccharin(Sigma Chemical Co., St. Louis, Mo.) was added to water or ethanolsolutions to achieve a concentration of 0.2% w/v. Standard operantchambers (Med Associates, VT) housed in sound-attenuated chambers wereused for ethanol self-administration. Syringe pumps dispensed ethanoland water into two stainless steel reservoirs mounted 4 cm above thefloor of the chamber, centered between the two operant levers. The tworetractable levers were located 4.5 cm to either side of the fluidreservoir. Fluid delivery and recording of operant responding werecontrolled by microcomputer. Rats were trained on a continuousreinforcement fixed-ratio 1 (FR1) schedule to self-administer oralalcohol (10% w/v, 0.1 ml per delivery) or water in 30 minute sessions.Rats were trained to lever press using a saccharine fading procedurewhereby a lever press resulted in the delivery of a saccharin solution.Over approximately 21 days, ethanol was introduced at increasingconcentrations and saccharine was removed. Once reliable levels ofalcohol-reinforced self-administration were achieved, the effect ofCompound (0, 5, 10 and 20 mg/kg) on maintenance levels of responding wasinvestigated.

Results: Compound A dose dependently reduced maintenance levels ofalcohol self-administration with significant reductions from baselinelevels observed at 20 mg/kg (p=0.0275; t=2.093; df=14). (see FIG. 2).Water consumption was not significantly altered at any dose tested,suggesting the effect of Compound A on response rates was specific toalcohol and not due to a general reduction in operant response rates.

EXAMPLE 4 Attenuation of Alcohol Deprivation (ADE) Effect FollowingInfusion of MC4R Agonist (Compound A)

Method: Methods for this experiment were as described in EXAMPLE 3.Following the maintenance ethanol self-administration experiment, ratswere re-baselined and once reliable levels of alcohol-reinforcedself-administration were achieved, rats were confined to their homecages for a 10-day period. Prior to reintroduction to the test chamber,animals were injected with Compound (0, 5, 10 and 20 mg/kg).

Results: Analysis of Variance revealed an overall significant effect ofdose (F [4.47]=7.6, p=0.0001). A dose dependent effect was observed inthe ADE experiment with 5 and 10 mg/kg blocking the ADE and 20 mg/kgleading to a significant decrease below baseline levels of consumption(see FIG. 3). Water consumption was not significantly altered at anydose tested, suggesting the effect of Compound A on response rates wasspecific to alcohol and not due to a general reduction in operantresponse rates.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the subject being treated for any ofthe indications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1-19. (canceled)
 20. A method selected from: a method of reducing alcohol consumption, a method of inhibiting alcohol consumption, a method of inhibiting the alcohol deprivation effect, a method of treating alcoholism and a method of treating alcohol abuse, comprising administering a therapeutically effective amount of a non-peptidyl melanocortin 4 receptor agonist to a subject in need thereof.
 21. The method of reducing alcohol consumption according to claim 20 comprising administering a therapeutically effective amount of a non-peptidyl melanocortin 4 receptor agonist to a subject in need thereof.
 22. The method of claim 21 wherein the non-peptidyl melanocortin 4 receptor agonist is a selective melanocortin 4 receptor agonist.
 23. The method of claim 21 wherein the melanocortin 4 receptor agonist is an orally active melanocortin 4 receptor agonist.
 24. The method of claim 22 wherein the melanocortin 4 receptor agonist has a selective functional activity characterized by an EC₅₀ at least 65-fold lower for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the melanocortin 2 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
 25. The method of claim 24 wherein the functional activity of the selective melanocortin 4 receptor agonist is characterized by an EC₅₀ at least 120-fold lower for the human melanocortin 4 receptor than for the human melanocortin 1 receptor.
 26. The method of claim 24 wherein the functional activity of the selective melanocortin 4 receptor agonist is characterized by an EC₅₀ at least 700-fold lower for the human melanocortin 4 receptor than for the human melanocortin 2 receptor.
 27. The method of claim 24 wherein the functional activity of the selective melanocortin 4 receptor agonist is characterized by an EC₅₀ at least 90-fold lower for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
 28. The method of claim 24 wherein the selective melanocortin 4 receptor agonist has a binding affinity index IC₅₀ value of less than 45 nM at the human melanocortin 4 receptor.
 29. The method of claim 21 wherein the melanocortin 4 receptor agonist is a compound of Formula I or II:

or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of: C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N, (CH₂)_(n)CON(R⁵R⁵), (CH₂)_(n)CO₂R⁵, (CH₂)_(n)COR⁵, (CH₂)_(n)NR⁵C(O)R⁵, (CH₂)_(n)NR⁵CO₂R⁵, (CH₂)_(n)NR⁵C(O)N(R⁵)₂, (CH₂)_(n)NR⁵SO₂R⁵, (CH₂)_(n)S(O)_(p)R⁵, (CH₂)_(n)SO₂N(R⁵)(R⁵), (CH₂)_(n)OR⁵, (CH₂)_(n)OC(O)R⁵, (CH₂)_(n)OC(O)OR⁵, (CH₂)_(n)OC(O)N(R⁵)₂, (CH₂)_(n)N(R⁵)(R⁵), and (CH₂)_(n)NR⁵SO₂N(R⁵)(R⁵), wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; Y is selected from the group consisting of: hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-heterocyclyl, wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; R¹ is selected from the group consisting of: hydrogen, amidino, C₁₋₄ alkyliminoyl, C₁₋₁₀ alkyl, (CH₂)_(n)—C₃₋₇ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, and (CH₂)_(n)-heteroaryl, wherein heteroaryl is selected from the group consisting of (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R² is selected from the group consisting of: phenyl, naphthyl, and heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; each R³ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R³ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R⁴ is independently selected from the group consisting of: hydrogen, C₁₋₆ alkyl, (CH₂)_(n) phenyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, and (CH₂)_(n)C₃₋₇ bicycloalkyl, wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, C₁₋₄ alkyl, hydroxy, and C₁₋₄ alkoxy; or two R⁴ groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇ cycloalkyl, wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; and wherein any methylene (CH₂) in R⁵ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two R⁵ groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁶ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; r is 1 or 2; s is 0, 1, or 2; n is 0, 1 or 2; and p is 0, 1, or
 2. 30. The method of claim 29 wherein X is phenyl substituted with two groups independently selected from R³, Y is hydrogen, and R¹ is tert-butyl, and R² is phenyl substituted with two groups independently selected from R³, or a pharmaceutically acceptable salt thereof.
 31. The method of claim 30 wherein the melanocortin 4 receptor agonist of Formula I is

or a pharmaceutically acceptable salt thereof.
 32. The method of inhibiting alcohol consumption according to claim 20 comprising administering a non-peptidyl melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, to a subject in need thereof wherein the melanocortin 4 receptor agonist is a compound of Formula I or II:

or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of: C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N, (CH₂)_(n)CON(R⁵R⁵), (CH₂)_(n)CO₂R⁵, (CH₂)_(n)COR⁵, (CH₂)_(n)NR⁵C(O)R⁵, (CH₂)_(n)NR⁵CO₂R⁵, (CH₂)_(n)NR⁵C(O)N(R⁵)₂, (CH₂)_(n)NR⁵SO₂R⁵, (CH₂)_(n)S(O)_(p)R⁵, (CH₂)_(n)SO₂N(R⁵)(R⁵), (CH₂)_(n)OR⁵, (CH₂)_(n)OC(O)R⁵, (CH₂)_(n)OC(O)OR⁵, (CH₂)_(n)OC(O)N(R⁵)₂, (CH₂)_(n)N(R⁵)(R⁵), and (CH₂)_(n)NR⁵SO₂N(R⁵)(R⁵), wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; Y is selected from the group consisting of: hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-heterocyclyl, wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; R¹ is selected from the group consisting of: hydrogen, amidino, C₁₋₄ alkyliminoyl, C₁₋₁₀ alkyl, (CH₂)_(n)—C₃₋₇ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, and (CH₂)_(n)-heteroaryl, wherein heteroaryl is selected from the group consisting of (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R² is selected from the group consisting of: phenyl, naphthyl, and heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; each R³ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R³ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R⁴ is independently selected from the group consisting of: hydrogen, C₁₋₆ alkyl, (CH₂)_(n) phenyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, and (CH₂)_(n)C₃₋₇ bicycloalkyl, wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, C₁₋₄ alkyl, hydroxy, and C₁₋₄ alkoxy; or two R⁴ groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇ cycloalkyl, wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; and wherein any methylene (CH₂) in R⁵ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two R⁵ groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁶ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; r is 1 or 2; s is 0, 1, or 2; n is 0, 1 or 2; and p is 0, 1, or
 2. 33. The method of inhibiting the alcohol deprivation effect in a subject in need thereof according to claim 20 comprising administering a non-peptidyl melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, to a subject in need thereof wherein the melanocortin 4 receptor agonist is a compound of Formula I or II:

or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of: C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N, (CH₂)_(n)CON(R⁵R⁵), (CH₂)_(n)CO₂R⁵, (CH₂)_(n)COR⁵, (CH₂)_(n)NR⁵C(O)R⁵, (CH₂)_(n)NR⁵CO₂R⁵, (CH₂)_(n)NR⁵C(O)N(R⁵)₂, (CH₂)_(n)NR⁵SO₂R⁵, (CH₂)_(n)S(O)_(p)R⁵, (CH₂)_(n)SO₂N(R⁵)(R⁵), (CH₂)_(n)OR⁵, (CH₂)_(n)OC(O)R⁵, (CH₂)_(n)OC(O)OR⁵, (CH₂)_(n)OC(O)N(R⁵)₂, (CH₂)_(n)N(R⁵)(R⁵), and (CH₂)_(n)NR⁵SO₂N(R⁵)(R⁵), wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; Y is selected from the group consisting of: hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-heterocyclyl, wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; R¹ is selected from the group consisting of: hydrogen, amidino, C₁₋₄ alkyliminoyl, C₁₋₁₀ alkyl, (CH₂)_(n)—C₃₋₇ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, and (CH₂)_(n)-heteroaryl, wherein heteroaryl is selected from the group consisting of (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R² is selected from the group consisting of: phenyl, naphthyl, and heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; each R³ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R³ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R⁴ is independently selected from the group consisting of: hydrogen, C₁₋₆ alkyl, (CH₂)_(n) phenyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, and (CH₂)_(n)C₃₋₇ bicycloalkyl, wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, C₁₋₄ alkyl, hydroxy, and C₁₋₄ alkoxy; or two R⁴ groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇ cycloalkyl, wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; and wherein any methylene (CH₂) in R⁵ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two R⁵ groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁶ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; r is 1 or 2; s is 0, 1, or 2; n is 0, 1 or 2; and p is 0, 1, or
 2. 34. The method of treating alcoholism according to claim 20 comprising administering a non-peptidyl melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, to a subject in need thereof wherein the melanocortin 4 receptor agonist is a compound of Formula I or II:

or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of: C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N, (CH₂)_(n)CON(R⁵R⁵), (CH₂)_(n)CO₂R⁵, (CH₂)_(n)COR⁵, (CH₂)_(n)NR⁵C(O)R⁵, (CH₂)_(n)NR⁵CO₂R⁵, (CH₂)_(n)NR⁵C(O)N(R⁵)₂, (CH₂)_(n)NR⁵SO₂R⁵, (CH₂)_(n)S(O)_(p)R⁵, (CH₂)_(n)SO₂N(R⁵)(R⁵), (CH₂)_(n)OR⁵, (CH₂)_(n)OC(O)R⁵, (CH₂)_(n)OC(O)OR⁵, (CH₂)_(n)OC(O)N(R⁵)₂, (CH₂)_(n)N(R⁵)(R⁵), and (CH₂)_(n)NR⁵SO₂N(R⁵)(R⁵), wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; Y is selected from the group consisting of: hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-heterocyclyl, wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; R¹ is selected from the group consisting of: hydrogen, amidino, C₁₋₄ alkyliminoyl, C₁₋₁₀ alkyl, (CH₂)_(n)—C₃₋₇ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, and (CH₂)_(n)-heteroaryl, wherein heteroaryl is selected from the group consisting of (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R² is selected from the group consisting of: phenyl, naphthyl, and heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; each R³ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R³ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R⁴ is independently selected from the group consisting of: hydrogen, C₁₋₆ alkyl, (CH₂)_(n) phenyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, and (CH₂)_(n)C₃₋₇ bicycloalkyl, wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, C₁₋₄ alkyl, hydroxy, and C₁₋₄ alkoxy; or two R⁴ groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇ cycloalkyl, wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; and wherein any methylene (CH₂) in R⁵ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two R⁵ groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁶ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; r is 1 or 2; s is 0, 1, or 2; n is 0, 1 or 2; and p is 0, 1, or
 2. 35. The method of treating alcohol abuse according to claim 20 comprising administering a non-peptidyl melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, to a subject in need thereof wherein the melanocortin 4 receptor agonist is a compound of Formula I or II:

or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of: C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N, (CH₂)_(n)CON(R⁵R⁵), (CH₂)_(n)CO₂R⁵, (CH₂)_(n)COR⁵, (CH₂)_(n)NR⁵C(O)R⁵, (CH₂)_(n)NR⁵CO₂R⁵, (CH₂)_(n)NR⁵C(O)N(R⁵)₂, (CH₂)_(n)NR⁵SO₂R⁵, (CH₂)_(n)S(O)_(p)R⁵, (CH₂)_(n)SO₂N(R⁵)(R⁵), (CH₂)_(n)OR⁵, (CH₂)_(n)OC(O)R⁵, (CH₂)_(n)OC(O)OR⁵, (CH₂)_(n)OC(O)N(R⁵)₂, (CH₂)_(n)N(R⁵)(R⁵), and (CH₂)_(n)NR⁵SO₂N(R⁵)(R⁵), wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; Y is selected from the group consisting of: hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-heterocyclyl, wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R⁶; alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R⁶ and oxo; and wherein any methylene (CH₂) in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; R¹ is selected from the group consisting of: hydrogen, amidino, C₁₋₄ alkyliminoyl, C₁₋₁₀ alkyl, (CH₂)_(n)—C₃₋₇ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, and (CH₂)_(n)-heteroaryl, wherein heteroaryl is selected from the group consisting of (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R² is selected from the group consisting of: phenyl, naphthyl, and heteroaryl, wherein heteroaryl is selected from the group consisting of: (1) pyridinyl, (2) furyl, (3) thienyl, (4) pyrrolyl, (5) oxazolyl, (6) thiazolyl, (7) imidazolyl, (8) pyrazolyl, (9) isoxazolyl, (10) isothiazolyl, (11) pyrimidinyl, (12) pyrazinyl, (13) pyridazinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, and (21) benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; each R³ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R³ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R⁴ is independently selected from the group consisting of: hydrogen, C₁₋₆ alkyl, (CH₂)_(n) phenyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, and (CH₂)_(n)C₃₋₇ bicycloalkyl, wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, C₁₋₄ alkyl, hydroxy, and C₁₋₄ alkoxy; or two R⁴ groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇ cycloalkyl, wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³; alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; and wherein any methylene (CH₂) in R⁵ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two R⁵ groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁶ is independently selected from the group consisting of: C₁₋₆ alkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁴, (CH₂)_(n)N(R⁴)₂, (CH₂)_(n)C≡N, (CH₂)_(n)CO₂R⁴, NO₂, (CH₂)_(n)NR⁴SO₂R⁴, (CH₂)_(n)SO₂N(R⁴)₂, (CH₂)_(n)S(O)_(p)R⁴, (CH₂)_(n)NR⁴C(O)N(R⁴)₂, (CH₂)_(n)C(O)N(R⁴)₂, (CH₂)_(n)NR⁴C(O)R⁴, (CH₂)_(n)NR⁴CO₂R⁴, (CH₂)_(n)NR⁴C(O)-heteroaryl, (CH₂)_(n)C(O)NR⁴N(R⁴)₂, (CH₂)_(n)C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_(n)C(O)N(R⁴)₂, CF₃, CH₂CF₃, OCF₃, and OCH₂CF₃, in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C₁₋₄ alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂) carbon atom in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on the same methylene (CH₂) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; r is 1 or 2; s is 0, 1, or 2; n is 0, 1 or 2; and p is 0, 1, or
 2. 